Neural stem cells for disease modeling of Wolman disease and evaluation of therapeutics
| Autor: | Jeanette Beers, Francis Aguisanda, Rong Li, Jizhong Zou, Catherine Z. Chen, Wei Zheng, Natasha Thorne, Charles D. Yeh |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cellular differentiation Cell Blotting Western Tocopherols lcsh:Medicine Lysosomal storage disease Biology Dermal fibroblast 03 medical and health sciences Lysosomal-Associated Membrane Protein 2 medicine Humans Pharmacology (medical) Induced pluripotent stem cell Genetics (clinical) Cells Cultured Skin Wolman disease Neural stem cells Research lcsh:R Cell Differentiation General Medicine Enzyme replacement therapy medicine.disease Phenotype Immunohistochemistry Neural stem cell 2-Hydroxypropyl-beta-cyclodextrin Lipoproteins LDL Induced pluripotent stem cells 030104 developmental biology medicine.anatomical_structure Cholesterol Immunology Cancer research Cell-based disease model |
| Zdroj: | Orphanet Journal of Rare Diseases, Vol 12, Iss 1, Pp 1-13 (2017) Orphanet Journal of Rare Diseases |
| ISSN: | 1750-1172 |
| DOI: | 10.1186/s13023-017-0670-9 |
| Popis: | Background Wolman disease (WD) is a rare lysosomal storage disorder that is caused by mutations in the LIPA gene encoding lysosomal acid lipase (LAL). Deficiency in LAL function causes accumulation of cholesteryl esters and triglycerides in lysosomes. Fatality usually occurs within the first year of life. While an enzyme replacement therapy has recently become available, there is currently no small-molecule drug treatment for WD. Results We have generated induced pluripotent stem cells (iPSCs) from two WD patient dermal fibroblast lines and subsequently differentiated them into neural stem cells (NSCs). The WD NSCs exhibited the hallmark disease phenotypes of neutral lipid accumulation, severely deficient LAL activity, and increased LysoTracker dye staining. Enzyme replacement treatment dramatically reduced the WD phenotype in these cells. In addition, δ-tocopherol (DT) and hydroxypropyl-beta-cyclodextrin (HPBCD) significantly reduced lysosomal size in WD NSCs, and an enhanced effect was observed in DT/HPBCD combination therapy. Conclusion The results demonstrate that these WD NSCs are valid cell-based disease models with characteristic disease phenotypes that can be used to evaluate drug efficacy and screen compounds. DT and HPBCD both reduce LysoTracker dye staining in WD cells. The cells may be used to further dissect the pathology of WD, evaluate compound efficacy, and serve as a platform for high-throughput drug screening to identify new compounds for therapeutic development. Electronic supplementary material The online version of this article (doi:10.1186/s13023-017-0670-9) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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